Spondyloarthritis (Spa) also known as spondyloarthropathy or spondylitis identifies a group of diseases primarily affecting the spine (spondylo) and other joints. This group of diseases is also identified as seronegative spondyloarthritis. The term “seronegative” refers to the fact that usually no rheumatoid factors are present in the blood. The group of Spa can be divided into Ankylosing Spondylitis (AS), reactive arthritis and its special manifestation, Reiter syndrome, and into psoriatic arthritis (PsA), enteropathic arthritis and undifferentiated spondyloarthritis. Several of these diseases may also manifest only as peripheral arthritis without inflammation of the axial skeleton. In view of the fact that this group of diseases is a seronegative disease, early diagnosis is difficult as detailed below.
Ankylosing spondylitis (AS) also known as Morbus Bechterew is a common, inflammatory rheumatoid disease which primarily affects the axial skeleton and is associated with sacroiliitis, uveitis and enthesitis. It affects in excess of 0.1% of the population and can be associated with uveitis, apical pulmonary fibrosis and cardiac disease. AS is a member of the group of seronegative spondyloarthropathies. It is believed that genetic predisposition is given. Further, it is described in the literature that AS is an autoimmune disease. Typically, joints in the spine and the sacroilium in the pelvis are affected. Eventually, fusion of the spine may occur. The aetiology of AS is unknown, but it is thought to be immune mediated. For example, autoimmune phenomena against the proteoglycan aggrocan are described. Typically, first symptoms of the disease appears between the age of 20 to 25. Untreated patients usually suffer from morning stiffness in the lower part of the spine or sometimes the entire spine often with pain referred to one or other buttock or the back of thigh from the sacroiliac joint. Men are affected more than women. Interestingly, AS is associated with an inflammation of the eye (iridocyclitis and uveitis) in about 40% of cases.
In the course of the disease, the spine gets porous which eventually lead to rupture of the vertebrae. It is assumed that about 1.75% of the adults have a prevalence for developing AS and undifferentiated spondyloarthritis.
Diagnosis of Spa, like AS and undifferentiated spondyloarthritis, represents a challenging task for laboratory diagnosis. It is quite common for the diagnosis of Spa, like AS and undifferentiated spondyloarthritis, to be missed or remarkably delayed, particularly, in the primary care setting. For example, on average, there is a 7-10 year delay in the diagnosis of AS from the onset of symptoms. The reason for this delay is the fact that there is no direct test to diagnose Spa, like AS. Hence, Spa, like AS, undifferentiated spondyloarthritis or PsA, must be diagnosed by differential diagnosis excluding other disease with similar symptoms, like osteoarthritis, osteoporosis, herniated disk or bacterial infections. Today, clinical examination in X-ray studies of the spine which show characteristic spinal changes and sacroilitis are the major diagnostic tools. However, X-ray studies lead to a long delay in diagnosis since the X-ray evident changes occur only after several years of onset of the disease. Although magnet resonance imaging may allow to establish early diagnosis, magnet resonance diagnosis is expensive and not every patient having pain would be diagnosed by magnetic resonance spectrometry further.
Although there is a need for diagnostic markers of Spa, like AS and undifferentiated spondyloarthritis, in particular of markers allowing early diagnosis of said diseases, no specific marker has been established yet. Several potential diagnostic markers have been described in the art. For example, variations of the HLA-B gene increase the risk of developing AS, although it is not a diagnostic test. It has been described that subjects with HLA-B27 variant are at higher risk than the general population of developing the disorder. HLA-B27 positive subjects are also indicative for other types of diseases, like Morbus Reiter as well as psoriatic arthritis but also for seropositive rheumatoid arthritis. Even 10% of healthy individuals carry the HLA-B27 antigen. Thus, false positive diagnosis may occur and the specificity of HLA-B27 for Spa, in particular, for AS and undifferentiated spondyloarthritis, is low.
Recently, anti-agalactosyl IgG antibodies in AS and psoriatic arthritis (PsA) have been described, Chou, C.-L., et al., Clin Rheumatol, 2010, DOI 10.1007/s10067-010-1413-7. However, the anti-agalactosyl IgG antibody described therein has also been described as a useful serological marker for rheumatoid arthritis. In addition, in seronegative spondyloarthropathy for which AS and PsA are representatives anti-agalactosyl IgG antibodies have been detected as well. Hence, anti-agalactosyl IgG antibody does not allow to discriminate between AS and PsA and between AS and other inflammatory rheumatic disorders.
Moreover, WO 2010/037184 describes diagnostic markers for AS. Therein, diagnostic methods and agents for diagnosing the presence or risk of development of AS in mammals are described. Said diagnostic methods and agents are based on the detection of polymorphisms within various genes. The diagnostic markers and the diagnostic test described therein are based on nucleic acid molecule detection or protein detection of the respective genes and proteins.
Very recently, screening and evaluating the mimic peptide as a useful serum biomarker of AS using the phage display technique has been described by Wang, M., et al., Rheumatol Int, DOI 10.1007/s00296-010-1403-8. Therein, the authors disclose a peptide sequence named AS1 which should represent a useful peptide reacting with sera of AS patients and, thus, may be a candidate for a specific serum biomarker. It is identified therein that the short peptide has no significant similarity with other sequences. Wright, C., et al., 2010, Mol Cell Proteomics, DOI 10.1074, mcp 11900384-MCP200, shows the detection of multiple autoantibodies in patients with AS using nucleic acid programmable protein assays.
In view of the above, there is an ongoing need for providing a diagnostic tool and method allowing diagnosis and assessing the risk of developing Spa, like AS and undifferentiated spondyloarthritis, as well as a tool and method for therapy control of Spa, like AS and undifferentiated spondyloarthritis. In addition, this tool, e.g. a kit, or method should preferably allow to differentiate between different seronegative spondyloarthropathies. In particular, the diagnostic marker may allow to differentiate between AS and PsA and between AS and other inflammatory rheumatic disorders.